The goal of this technology development project is to construct an instrument that measures simultaneously the mass and a two-dimensional fingerprint of the structure of biologically relevant molecules. The instrument is expected to greatly expand the utility of currently available mass spectrometers. This goal will be accomplished by inserting a proprietary structure-sensitive ionization method into existing mass spectrometer designs. The structure-sensitive mass spectrometer will find many uses in biomedical research. For example, it will enable researchers to rapidly observe and follow folding and/or mis-folding events of proteins implicated in diseases. In addition, proteomics research in general will benefit from the possibility to catalog a shape-and mass fingerprint library of proteins. The instrument development project is partitioned into two phases. During the first phase (R21), the design concepts are refined, a feasibility calculation is prepared, and designs are completed. Particular attention, at this point, is directed toward designing a flexible instrument that permits the experimental fine-tuning of the parameter space of the instrument. The prototype instrument is built during the second phase (R33). The inherent flexibility of the prototype allows the exploration of the parameters that optimize the performance. Bovine pancreatic trypsin inhibitor and model synthetic peptides are used as test systems. The goal of this pancreatic trypsin inhibitor and model synthetic peptides are used as test systems. The goal of this phase is to evaluate the structure specificity of the instrument, and to derive a set of parameters to guide the development of a commercial instrument with operating characteristics similar to those of existing mass spectrometers. This includes ease of use, rapid turn-around, and the possibility to automate and systematize the instrument. Commercial implementation will be sought by partnering with existing manufacturers of related equipment.